The present invention relates to a novel pyridine derivative or a salt thereof, which inhibits collagen synthesis, and a pharmaceutical containing said compound, which is useful for prophylaxis or treatment of fibrosis.
At present, it is said that 130 or more types of diseases exist as diseases referred to as fibrosis, including rare diseases. Typical disease of fibrosis includes, for example, pulmonary fibrosis, hepatic fibrosis, glomerulosclerosis, etc.
Pulmonary fibrosis generally refers to syndrome wherein the function of lung is lost because of reconstructed lesion in the alveror region, that is, an alveolar structure is broken by the inflammatory reaction to cause growth of fibroblasts and excess increase in extracellular matrix composed mainly of collagen, resulting in lung sclerosis.
On the other hand, hepatic fibrosis refers to the condition of diseases wherein necrosis of hepatocytes is caused by various hepatopathy such as chronic virus hepatitis, alcoholic hepatopathy, etc. and, thereafter, extracellular matrix increases to recruit for the site, resulting in hepatic fibrogenesis. The terminal status of this condition of disease leads to liver cirrhosis wherein the whole liver tissue atrophies and scleroses.
Conventional drugs which inhibit hepatic fibrogenesis described above includes, for example, penicillamine known as a remedy for Wilkinson""s disease which occurs due to accumulation of copper in liver as a result of abnormal metabolism of copper, Lufironil which has been studied as a proline hydroxylase inhibitor, etc.
However, these drugs are not sufficient as a drug for preventing hepatic fibrogenesis in view of side effects and validity. At present, a remedy (or therapy) which is effective for fibrosis represented by hepatic fibrogenesis has not been established, and it has been studied how the process of causing fibrogenesis is specifically inhibited.
As described above, it has been known that an excess increase in extracellular matrix composed mainly of collagen occurs in the process of causing fibrogenesis in lung tissues and hapatocytes. It has also been known that an increase in extracellular matrix in hepatocytes mainly occurs in a sinusoid wall Disse space and that Ito cells as mesenchymal cells of liver constitute a main production source.
Accordingly, it is important that an excess increase in extracellular matrix (i.e. collagen) is inhibited to inhibit fibrogenesis in liver, lung, etc.
Thus, an object of the present invention is to provide a novel compound which is superior in effect of inhibiting production of collagen, and a pharmaceutical containing the same, which is useful for prophylaxis or treatment of fibrosis.
The present inventors have intensively studied to solve the problems described above. As a result, they have obtained such a knowledge that a pyridine derivative represented by the general formula (1) described below and a pharmaceutically acceptable salt thereof are superior in effect of inhibiting collagen production, thus completing the present invention.
Thus, the present invention mainly relates to:
(1) A pyridine derivative represented by the general formula (1): 
wherein R1 represents a halogen atom or a halogen-substituted lower alkyl group; R2 and R3 are the same or different and represent a hydrogen atom or a halogen atom; V represents a group: xe2x80x94C(xe2x95x90O)xe2x80x94H, a group: xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, a group: xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94or a group: xe2x80x94CHxe2x95x90CHxe2x80x94; A represents a group A1: 
(wherein R4 represents a hydrogen atom, a lower alkanoyl group, a benzoyl group, a 2-lower alkyl-1,3-dioxolane group or a hydroxy-substituted lower alkyl group; R5 represents a hydrogen atom, a 2-lower alkyl-1,3-dioxolane group, a lower alkyl group or a lower alkanoyl group; and R6 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group), a group A2: 
(wherein R7 represents a hydrogen atom or a lower alkyl group; and R8 is the same or different and represents a hydrogen atom, a hydroxyl group, an oxo group, a lower alkanoyloxy group, an aroyloxy group, a lower alkoxy group, a group: 
(wherein k represents an integer of 1 to 3) or a group: xe2x95x90Nxe2x80x94OR10 (R10 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group); p represents an integer of 1 to 2;
represents a single bond or a double bond; Y represents a group: xe2x80x94(CH2)mxe2x80x94, a group: xe2x95x90CH(CH2)m-1xe2x80x94 or a group: xe2x80x94(CH2)m-1CHxe2x95x90; and m represents an integer of 1 to 3) or a group A3: 
(wherein R9 is the same or different and represents a hydrogen atom, a hydroxyl group, an oxo group, a lower alkanoyloxy group, an aroyloxy group, a lower alkoxy group, a group: 
(wherein k represents an integer of 1 to 3) or a group: xe2x95x90Nxe2x80x94OR10 (R10 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group); q represents an integer of 1 to 2; represents a single bond or a double bond; Z represents a group: xe2x80x94(CH2)nxe2x80x94, a group: xe2x95x90CH(CH2)n-1xe2x80x94 or a group: xe2x80x94(CH2)n-1CHxe2x95x90; and n represents an integer of 1 to 3)] or a salt thereof;
(2) A pharmaceutical comprising a compound of the general formula (1) in claim 1 or a pharmaceutically acceptable salt thereof;
(3) A pharmaceutical composition for prophylaxis or treatment of fibrosis, which comprises an effective amount of a compound of the general formula (1) in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent and/or excipient; and
(4) A method for inhibiting fibrogenesis caused by excess production of collagen in a mammal which comprises administering to said mammal a pharmaceutically effective amount of a compound of the general formula (1) in claim 1 or a pharmaceutically acceptable salt thereof.
The pyridine derivative (1) or a pharmaceutically acceptable salt thereof are superior in effect of inhibiting collagen production, as described above, and has characteristics such as long duration time of drug efficacy, good transition in blood and low toxicity.
Accordingly, the pyridine derivative (1) or a salt thereof is effective for prophylax or treatment of diseases attended with fibrogenesis caused by excess production of collagen, for example, (i) organ diseases such as sudden and interstitial pulmonary fibrosis, pneumoconiosis, ARDS, hepatic fibrosis, neonatal hepatic fibrosis, hepatic cirrhosis, mucoviscidosis and myelofibrosis; (ii) dermal diseases such as scleroderma, elephantiasis, morphea, injury and hypertrophic cicatrix and keloid after burn injury; (iii) vascular diseases such as atherosclerosis and arteriosclerosis; (iv) ophthalmic diseases such as diabetic retinopathy, fibroplasia retrolentalis, vascularization arising along with corneal transplantation, glaucoma, proliferative vitreoretinopathy and corneal cicatrix after operation; (v) renal diseases such as contracted kidney, nephrosclerosis, interstitial nephritis, IgA nephritis, glomerulosclerosis, membranoproliferative nephritis, diabetic nephropathy, chronic interstitial nephritis and chronic glomerulonephritis; and (vi) diseases in cartilage or bone, such as rheumatic arthritis, chronic arthritis and osteoarthritis.
Among them, the pyridine derivative (1) and a salt thereof of the present invention is superior in effect of inhibiting fibrogenesis attended with the organ diseases listed in the above item (i), and can be used as a preventive or a remedy for pulmonary fibrosis and hepatic fibrosis.
The pyridine derivative represented by the general formula (1) of the present invention includes, for example, the following compounds:
(1-1) a pyridine derivative wherein R1 to R3, R7 to R10, m, n, p, q, k, V, Y and Z are as defined in the general formula (1) and A is a group A2 or a group A3, or a pharmaceutically acceptable salt thereof;
(1-2) a pyridine derivative, wherein R1 to R6 and V are as defined in the general formula (1) and A is a group A1, or a pharmaceutically acceptable salt thereof;
(1-3) a pyridine derivative wherein R1 to R3, R7 to R8, m, p, k, V and Y are as defined in the general formula (1) and A is a group A2, or a pharmaceutically acceptable salt thereof;
(1-4) a pyridine derivative wherein R1 to R3, R9, R10, n, q, k, V and Z are as defined in the general formula (1) and A is a group A3, or a pharmaceutically acceptable salt thereof;
(1-5) a pyridine derivative wherein R1 to R10, m, n, p, q, k, A, Y and Z are as defined in the general formula (1), V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 or xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, or a pharmaceutically salt thereof;
(1-6) a pyridine derivative wherein R to R m, n, p, q, k, A, Y and Z are as defined in the general formula (1) and V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-7) a pyridine derivative wherein R1 to R10, m, n, p, q, k, A, Y and Z are as defined in the general formula (1) and V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-8) a pyridine derivative wherein R1 to R10, m, n, p, q, k, A, Y and Z are as defined in the general formula (1) and V is a group,xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-9) a pyridine derivative wherein R1 to R3, R1 to R10, n, m, p, q, k, Y and Z are as defined in the general formula (1), V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 and A is a group A2 or a group A3, or a pharmaceutically acceptable salt thereof;
(1-10) a pyridine derivative wherein R1 to R6 are as defined in the general formula (1) and V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-11) a pyridine derivative wherein R1 to R3, R7, R8, m, p, k and Y are as defined in the general formula (1), V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 and A is a group A2, or a pharmaceutically acceptable salt thereof;
(1-12) a pyridine derivative wherein R1 to R3, R7, R8, m, p, k and Y are as defined in the general formula (1), V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 and A is a group A2, or a pharmaceutically acceptable salt thereof;
(1-13) a pyridine derivative wherein R1 to R3, R9, R10, q, k, n and Z are as defined in the general formula (1), V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 and A is a group A3, or a pharmaceutically acceptable salt thereof;
(1-14) a pyridine derivative wherein R1 to R3, R7 to R10, n, m, p, q, k, Y and Z are as defined in the general formula (1), V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 and A is a group A2 or a group A3, or a pharmaceutically acceptable salt thereof;
(1-15) a pyridine derivative wherein R1 to R6 are as defined in the general formula (1), V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94and A is a group A1, or a pharmaceutically acceptable salt thereof;
(1-16) a pyridine derivative wherein R1 to R3, R7, R81 m, p, k and Y are as defined in the general formula (1), V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 and A is a group A2, or a pharmaceutically acceptable salt thereof;
(1-17) a pyridine derivative wherein R1 to R3, R9, R10, n, q, k and Z are as defined in the general formula (1), V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 and A is a group A3, or a pharmaceutically acceptable salt thereof;
(1-18) a pyridine derivative wherein R3 to R10, n, m, p, q, k, V, Y, Z and A are as defined in the general formula (1) and R1 and R2 are respectively a halogen atom, or a pharmaceutically acceptable salt thereof;
(1-19) a pyridine derivative wherein R2 to R10, n, m, p, q, k, V, Y, Z and A are as defined in the general formula (1) and R1 is a halogen-substituted lower alkyl group, or a pharmaceutically acceptable salt thereof;
(1-20) a pyridine derivative wherein R2, R3, R7 to R10, n, m, p, q, k, V, Y and Z are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group and A is a group A2 or a group A3, or a pharmaceutically acceptable salt thereof;
(1-21) a pyridine derivative wherein R2 and R3 to R6 are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group and A is a group A1, or a pharmaceutically acceptable salt thereof;
(1-22) a pyridine derivative wherein R2, R3, R7, R8, m, p, k, V and Y are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group and A is a group A2, or a pharmaceutically acceptable salt thereof;
(1-23) a pyridine derivative wherein R2, R3, R9, R10, n, q, k, V and Z are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group and A is a group A3, or a pharmaceutically acceptable salt thereof;
(1-24) a pyridine derivative wherein R3, R7 to R10, n, m, p, q, k, V, Y and Z are as defined in the general formula (1), R1 and R2 are respectively a halogen atom and A is a group A2 or a group A3, or a pharmaceutically acceptable salt thereof;
(1-25) a pyridine derivative wherein R3 to R6 and V are as defined in the general formula (1), R1 and R2 are respectively a halogen atom and A is a group A1, or a pharmaceutically acceptable salt thereof;
(1-26) a pyridine derivative wherein R3, R7, R8, m, p, k, V and Y are as defined in the general formula (1), R1 and R2 are respectively a halogen atom and A is a group A2, or a pharmaceutically acceptable salt thereof;
(1-27) a pyridine derivative wherein R3, R9, R10, n, q, k, V and Z are as defined in the general formula (1), R1 and R2 are respectively a halogen atom and A is a group A3, or a pharmaceutically acceptable salt thereof;
(1-28) a pyridine derivative wherein R2, R3, R7 to R10, n, m, p, q, k, Y and Z are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group, A is a group A2 or a group A3 and V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-29) a pyridine derivative wherein R2 to R6 are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group, A is a group A1 and V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-30) a pyridine derivative wherein R2, R3, R7, R8, m, p, k and Y are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group, A is a group A2 and V is a group xe2x80x94C(=O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-31) a pyridine derivative wherein R2, R3, R9, R10, n, q, k and Z are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group, A is a group A3 and V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-32) a pyridine derivative wherein R3, R7 to R10 n, m, p, q, k, Y and Z are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A2 or a group A3 and V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-33) a pyridine derivative wherein R3 to R6 are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A1 and V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-34) a pyridine derivative wherein R3, R7, R8, m, p, k and Y are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A and V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-35) a pyridine derivative wherein R3, R9, R1 n, q, k and Z are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A3 and V is a group xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-36) a pyridine derivative wherein R2, R3, R7 to R10, n, m, p, q, k, Y and Z are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group, A is a group A2 or a group A3 and V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-37) a pyridine derivative wherein R2, R3, R7 to R10, n, m, p, q, k, Y,and Z are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group, A is a group A2 or a group A3 and V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-38) a pyridine derivative wherein R2 to R6 are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group, A is a group A1 and V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-39) a pyridine derivative wherein R2, R3, R7, R8, m, p, k and Y are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group, A is a group A2 and V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-40) a pyridine derivative wherein R2, R3, R7, R8, m, p, k and Y are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group, A is a group A2 and V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-41) a pyridine derivative wherein R2, R3, R9, R10, n, q, k and Z are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group, A is a group A3 and V is a group xe2x80x94NHxe2x80x94C(xe2x80x94O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-42) a pyridine derivative wherein R3, R7 to R10, n, m, p, q, k, Y and Z are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A2 or a group A3 and V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-43) a pyridine derivative wherein R3 to R6 are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A1 and V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-44) a pyridine derivative wherein R3, R7, R8, m, p, k and Y are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A2 and V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-45) a pyridine derivative wherein R3, R9, R10, n, q, k and Z are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A3 and V is a group xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or a pharmaceutically acceptable salt thereof;
(1-46) a pyridine derivative wherein R1 to R3, R7 to R9, p, q, k, V, Y and Z are as defined in the general formula (1), A is a group A2 or a group A3 and m and n are respectively 1, or a pharmaceutically acceptable salt thereof;
(1-47) a pyridine derivative wherein R1 to R3, R7, R8, p, k, V and Y are as defined in the general formula (1), A is a group A2 and m is 1, or a pharmaceutically acceptable salt thereof;
(1-48) a pyridine derivative wherein R1 to R3, R9, R10, q, k, V and Z are as defined in the general formula (1), A is a group A3 and n is 1, or a pharmaceutically acceptable salt thereof;
(1-49) a pyridine derivative wherein R1 to R3, R7, p, q, k, V, Y and Z are as defined in the general formula (1), A is a group A2 or a group A3, m and n are respectively 1 and R8 and R9 are respectively an oxo group, or a pharmaceutically acceptable salt thereof;
(1-50) a pyridine derivative wherein R1 to R3, R7, p, q, k, V and Z are as defined in the general formula (1), A is a group A2 or A3, m and n are respectively 1, and R8 and R9 are respectively lower alkanoyoxy group, or a pharmaceutically acceptable salt thereof;
(1-51) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group, a lower alkanoyloxy group or a hydroxyl group, Y is a group: xe2x80x94(CH2)mxe2x80x94 or xe2x80x94(CH2)m-1CHxe2x95x90 and m is 1, or a pharmaceutically acceptable salt thereof;
(1-52) a pyridine derivative wherein R1 is a halogen-substituted lower alkyl group, R2 and R3 are respectively a hydrogen atom, V is a group: xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group or a lower alkanoyloxy group, Y is a group: xe2x80x94(CH2)mxe2x80x94 or xe2x80x94(CH2)m-1CHxe2x95x90 and m is 1, or a pharmaceutically acceptable salt thereof;
(1-53) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group or a lower alkanoyloxy group, Y is a group: xe2x80x94(CH2)mxe2x80x94 or xe2x80x94(CH2)m-1CHxe2x95x90 and m is 2, or a pharmaceutically acceptable salt thereof;
(1-54) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group or a lower alkanoyloxy group, Y is a group: xe2x80x94(CH2)mxe2x80x94 or xe2x80x94(CH2)m-1CHxe2x95x90 and m is 3, or a pharmaceutically acceptable salt thereof;
(1-55) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, A is a group A1, R4 is a 2-lower alkyl-1,3-dioxolane group, R5 is a hydrogen atom and R6 is a hydrogen atom, or a pharmaceutically acceptable salt thereof;
(1-56) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group or a lower alkanoyloxy group, Y is a group: xe2x80x94(CH2)mxe2x80x94 or xe2x80x94(CH2)m-1CHxe2x95x90 and m is 1 or 2, or a pharmaceutically acceptable salt thereof;
(1-57) a pyridine derivative wherein Z is as defined in the general formula (1), R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, A is a group A3, R9 is an oxo group or a lower alkanoyloxy group and n is 1, or a pharmaceutically acceptable salt thereof;
(1-58) a pyridine derivative wherein R1 is a halogen-substituted lower alkyl group, R2 and R3 are respectively a hydrogen atom, V is a group: xe2x80x94NHxe2x80x94C(xe2x80x94O)xe2x80x94NHxe2x80x94, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group or a lower alkanoyloxy group, Y is a group: xe2x80x94(CH2)mxe2x80x94 and m is 1, or a pharmaceutically acceptable salt thereof;
(1-59) a pyridine derivative wherein R1 is a halogen-substituted lower alkyl group, R2 and R3 are respectively a hydrogen atom, V is a group: xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group or a lower alkanoyloxy group, Y is a group: xe2x80x94(CH2)mxe2x80x94 and m is 1, or a pharmaceutically acceptable salt thereof;
(1-60) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, A is a group A2, R7 is a hydrogen atom, R8 is a hydrogen atom and Y is a group: xe2x95x90CH(CH2)m-1xe2x80x94 or a group: xe2x80x94(CH2m-1CHxe2x95x90, or a pharmaceutically acceptable salt thereof;
(1-61) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, A is a group A1, R4 is a hydrogen atom, R5 is a lower alkyl group and R6 is a lower alkyl group, or a pharmaceutically acceptable salt thereof;
(1-62) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, A is a group A1, R4 is a lower alkanoyl group and R5 and R6 are respectively a hydrogen atom, or a pharmaceutically acceptable salt thereof;
(1-63) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, A is a group A1, R4 is a lower alkanoyl group and R5 and R6 are respectively a hydrogen atom, or a pharmaceutically acceptable salt thereof;
(1-64) a pyridine derivative wherein R1 is a halogen-substituted lower alkyl group, R2 and R3 are respectively a hydrogen atom, V is a group: xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, A is a group A1, R4 is a lower alkanoyl group and R5 and R6 are respectively a hydrogen atom, or a pharmaceutically acceptable salt thereof;
(1-65) a pyridine derivative wherein R1 is a halogen-substituted lower alkyl group, R2 and R3 are respectively a hydrogen atom, V is a group: xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, A is a group A1, R4 is a lower alkanoyl group, R5 is a hydrogen atom or a lower alkyl group and R6 is a hydrogen atom, or a pharmaceutically acceptable salt thereof; and
(1-66) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, A is a group A2, Y is a group: xe2x80x94(CH2)mxe2x80x94, m is 1, R7 is a hydrogen atom or a lower alkyl group and R8 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
The respective groups shown in the general formula (1) are specifically explained as follows.
The lower alkyl group includes, for example, straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl and hexyl.
The hydroxy-substituted lower alkyl group includes, for example, hydroxy lower alkyl group whose alkyl moiety is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 1,1-dimethyl-2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxybutyl, 5-hydroxypentyl, 1-hydroxypentyl and 6-hydroxyhexyl.
The halogen-substituted lower alkyl group includes, for example, alkyl group having 1 to 6 carbon atoms which is substituted with 1 to 3 halogen atoms, such as monochloromethyl, monobromomethyl, monoiodomethyl, monofluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl, difluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, trifluoromethyl, monochloroethyl, monobromoethyl, monoiodoethyl, dichloroethyl, dibromoethyl, difluoroethyl, dichlorobutyl, diiodobutyl, difluorobutyl, chlorohexyl, bromohexyl and fluorohexyl.
The 2-lower alkyl-1,3-dioxolane group includes, for example, 2-lower alkyl-1,3-dioxolane group whose alkyl moiety is an alkyl group having 1 to 6 carbon atoms, such as 2-methyl-1,3-dioxolane, 2-ethyl-1,3-dioxolane and 2-propyl-1,3-dioxolane, 2-butyl-1,3-dioxolane and 2-hexyl-1,3-dioxolane.
The halogen atom include, for example, fluorine, chlorine, bromine and iodine.
The alkanoyl moiety of the lower alkanoyloxy group and lower alkanoyl group includes, for example, straight-chain or branched alkanoyl group whose alkyl moiety has 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, pentanoyl and hexanoyl.
The aroyl moiety of the aroyloxy group includes, for example, benzoyl, toluoyl, naphthoyl, salicyloyl, anisoyl and phenanthoyl.
The lower alkoxy group includes, for example, straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy and hexyloxy.
The process for producing the pyridine derivative (1) of the present invention will be explained below.
Reaction Scheme (I-a): 
(wherein R1, R2, R3 and A are as defined above)
This reaction is a process for obtaining a pyridine derivative (1-A) wherein V is xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94of the present invention. That is, the pyridine derivative (1-A) is obtained by condensing a carboxylic acid (2) with a 3-aminopyridine derivative (3) in a state free from solvent or in a suitable solvent, using a water-soluble carbodiimide such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride as a condensing agent or a carbodiimide such as N,N-dicyclohexylcarbodiimide (DCC).
In that case, when tertiary amine is added, basicity of the amine compound (3) is improved and, therefore, the reaction proceeds.
In the present invention, a condensing agent such as isobutyl chloroformate, diphenyl phosphinic chloride and carbonyl diimidazole may also be used in place of the carbodiimide.
The solvent may be any one which does not adversely affect the reaction, and examples thereof include an inert solvent such as tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, toluene and 1,2-dimethoxyethane.
The tertiary amine includes, for example, triethylamine, tributylamine, pyridine, N-methylmorpholine, quinoline, lutidine and 4-dimethylaminopyridine.
The condensing agent is used in the amount of at least 1 mol, and preferably from 1 to 5 mol, per mol of the compound (2).
The 3-aminopyridine derivative (3) is used in the amount of at least 1 mol, and preferably from 1 to 5 mol, per mol of the compound (2).
The reaction is usually carried out by adding the condensing agent to the carboxylic acid (2) at about xe2x88x9220 to 180xc2x0 C., and preferably 0 to 150xc2x0 C., for 5 minutes to 3 hours and further adding the 3-aminopyridine derivative (3), and the reaction is completed within about 30 minutes to 30 hours after adding 3-aminopyridine derivative (3).
Reaction Scheme (1-b): 
(wherein R1 to R3 and A are as defined above, and X represents a halogen atom)
This reaction is another process for obtaining the pyridine derivative (1-A). That is, the pyridine derivative (1-A) is obtained by reacting a carboxylic acid (2) with a suitable halogenating. agent in a state free from solvent or in a suitable solvent to obtain an acid halide (4), and reacting the acid halide (4) with a 3-aminopyridine derivative (3).
In that case, hydrogen halide is removed from the reaction system by adding tertiary amine and, therefore, the reaction proceeds.
The solvent used in this reaction includes, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbon such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbon such as benzene and toluene; and N,N-dimethylformamide (DMF).
The halogenating agent includes, for example, thionyl halide such as thionyl chloride and thionyl bromide; hydrogen halide such as hydrogen chloride, hydrogen bromide and hydrogen iodide; and phosphorous halide such as phosphorous trichloride and phosphorous tribromide.
The amount of the halogenating agent used is at least 1 mol, and preferably from 1 to 5 mol, per mol of the carboxylic acid (2).
The amount of the 3-aminopyridine derivative (3) used is at least 1 mol, and preferably from 1 to 5 mol, per mol of the acid halide (4).
The reaction is carried out at about xe2x88x9220 to 180xc2x0 C., and preferably from 0 to 150xc2x0 C., and is completed within about 5 minutes to 30 hours.
Reaction Scheme (II): 
(wherein R1, R2, R3 and A are as defined above) This reaction is a process for obtaining the pyridine derivative (1-B) wherein V is xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 of the present invention. That is, the pyridine derivative (1-B) of the present invention is obtained by reacting pyridinecarboxylic acid (5) with an aniline derivative (6) according to the process described in the above reaction scheme (I-a).
The solvent, tertiary amine and condensing agent used include, for example, those listed in the above reaction scheme (I-a).
The condensing agent is used in the amount of at least 1 mol, and preferably from 1 to 5 mol, per mol of the pyridinecarboxylic acid (5).
The aniline derivative (6) is used in the amount of at least 1 mol, and preferably from 1 to 5 mol, per mol of the pyridinecarboxylic acid (5).
The reaction is usually carried out by adding the condensing agent to the pyridinecarboxylic acid (5) at about xe2x88x9220 to 180xc2x0 C., and preferably 0 to 150xc2x0 C., for 5 minutes to 3 hours and further adding the aniline derivative (6), and the reaction is completed within about 30 minutes to 30 hours after adding the aniline derivative (6).
In the pyridine derivative (1) of the present invention, pyridine derivatives of the following items {circumflex over (1)} to {circle around (2)} may be produced by reducing a pyridine derivative (1-a) wherein at least one of R8 is an oxo group or a pyridine derivative (1-axe2x80x2) wherein at least one of R9 is an oxo group.
{circle around (1)} a pyridine derivative (1-b) wherein Y in the group A2 in A is a group: xe2x80x94(CH2)mxe2x80x94 and at least one of R8 is a hydroxyl group
{circle around (2)} a pyridine derivative (1-bxe2x80x2) wherein Z in the group A3 in A is a group: xe2x80x94(CH2)mxe2x80x94 and at least one of R9 is a hydroxyl group
For example, the pyridine derivative (1-b) of the item {circle around (1)} is obtained by reducing the pyridine derivative (1-a) wherein at least one of R8 is an oxo group in a suitable solvent, as shown in the following reaction scheme (III-a).
Reaction Scheme (III-a): 
(wherein R1, R2, R3, V, p and m are as defined above; R8a represents an oxo group; R8-8a represents a group wherein R8a is eliminated from R8; s represents 0 or 1, with the proviso that s represents 0 when n is 2; and R8b represents a hydroxyl group)
In the above reaction scheme, the case where A is a group A2 was illustrated, but the case where A is a group A3 can also be carried out in the same manner. Also in the following reaction scheme, the case where A is a group A2 was described, but the compound wherein A is a group A3 can also be synthesized by the corresponding reaction scheme.
The solvent may be any one which does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; halogenated hydrocarbon such as methylene chloride and chloroform; and aromatic hydrocarbon such as benzene and toluene.
The reduction process includes, for example, a catalytic reduction process in a suitable solvent, or a process using a reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride, diborane and raney nickel.
The reducing agent is usually used in the amount of 0.25 to 5 mol, and preferably from 1 to 3 mol, per mol of the pyridine derivative (1-a) in the case of one oxo group (R8a). In the case of two oxo groups (R8a), the reducing agent is usually used in the amount of 2 to 10 mol, and preferably from 2 to 6 mol. The reaction is usually carried out at 0 to 30xc2x0 C. and is completed within about 1 to 30 hours.
In the pyridine derivative (1) of the present invention, even if R8 in the group A2 or R9 in the group A3 of A is a group: xe2x95x90Nxe2x80x94OR10 (R10 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group), it may also be produced by using, as a starting material, a pyridine derivative (1-a) or (1-axe2x80x2) wherein R8 or R9 is an oxo group.
The process for producing pyridine derivatives (1-f-1) to (1-f-3) wherein R10 in the group: xe2x95x90Nxe2x80x94OR10 is a hydrogen group, a lower alkyl group or a lower alkanoyl group will be explained in order by way of R8 in the group A2 as the example.
First, a pyridine derivative (1-f-1) wherein R8 is a group: xe2x95x90Nxe2x80x94OH (R10 is a:hydrogen atom) is obtained by reacting the pyridine derivative (1-a) with hydroxylamine hydrochloride in a suitable solvent in the presence of a base, as shown in the following reaction scheme.
Reaction Scheme (III-b): 
(wherein R1, R2, R3, V, R8a, R8-8a, p, m and s are as defined above, and R8 represents a group: xe2x95x90Nxe2x80x94OH)
The solvent may be any one which does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; lower alcohols such as methanol, ethanol and isopropanol; and acetic acid and water.
The base includes, for example, trialkylamine such as triethylamine; alkali metal carbonate such as potassium carbonate, barium carbonate and sodium carbonate; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; and pyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), sodium acetate and piperidine. The amount of the base used is from 1 to 100 mol, and preferably from 2 to 10 mol, per mol of the pyridine derivative (1-a).
The amount of hydroxylamine hydrochloride used is from 1 to 50 mol, and preferably from 2 to 10 mol, per mol of the pyridine derivative (1-a). The reaction is usually carried out at xe2x88x9220 to 150xc2x0 C., and is completed within about 5 minutes to 24 hours.
Then, a pyridine derivative (1-f-2) wherein R8 is a group: xe2x95x90Nxe2x80x94OR10a (R10a represents a lower alkyl group) can be produced by reacting according to the same manner as that described in the reaction scheme (III-b) except for using O-alkylhydroxylamine hydrochloride in place of the above hydroxylamine hydrochloride.
For example, in the pyridine derivative (1-f-2), a pyridine derivative (1-f-21) wherein R10 is a methyl group can be produced by reacting according to the same manner as that described above except for using O-methylhydroxylamine hydrochloride in place of the above hydroxylamine hydrochloride.
A pyridine derivative (1-f-3) wherein R8 is a group: xe2x95x90Nxe2x80x94OR10b (R10b represents a lower alkanoyl group) is obtained by reacting the pyridine derivative (1-f-1), obtained from the pyridine derivative (1-a) wherein R8 is an oxo group according to the process described in the above reaction scheme (III-b), with an acylating agent in a suitable solvent as shown in the following reaction scheme (III-c). In that case, when tertiary amine is added, basicity of the pyridine derivative (1-f-1) is enhanced and, therefore, the reaction proceeds.
Reaction Scheme (III-c): 
(wherein R1 R2 R3, V, R8c, R8-8a, p, m and s are as defined above, and R8d represents a group: xe2x95x90Nxe2x80x94OR10b (R10b is as defined above).
The solvent may be any one which does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; halogenated hydrocarbon such as methylene chloride and chloroform; and aromatic hydrocarbon such as benzene and toluene; and dimethylformamide.
The acylating agent includes acid anhydride or acid halide corresponding to the lower alkanoyl group as for R10b, and examples thereof include acetic anhydride, acetyl halide, propionyl halide, isobutyryl halide, pivaloyl halide and hexanoyl halide.
Specifically explaining, acetic anhydride and acetyl halide (e.g. acetyl chloride, acetyl fluoride, acetyl iodide, acetyl bromide, etc.) may be used as the acylating agent to obtain a pyridine derivative (1-f-31) wherein R10b is an acetyl group in the above pyridine derivative (1-f-3).
The tertiary amine includes, for example, trialkylamine (e.g. triethylamine, etc.), pyridine, quinoline, lutidine, N-methylmorpholine, 4-dimethylaminopyridine and imidazole.
The amount of the acylating agent used is usually from 1 to 20 mol, and preferably from 1 to 5 mol, per mol of the pyridine derivative (1-f-1) in the case of one R8c. The amount of the acylating agent used is usually from 2 to 40 mol, and preferably from 2 to 10 mol, per mol of the pyridine derivative (1-f-1) in the case of two R8c. The reaction is usually carried out at xe2x88x9220 to 150xc2x0 C., and is completed within about 5 minutes to 24 hours.
Pyridine derivatives (1-fxe2x80x2-1) to (1-fxe2x80x2-3) wherein R9 in the group A3 is a group: xe2x95x90Nxe2x80x94OR10 (R10 is as defined above) is produced by reacting according to the same manner as that described in the above reaction schemes (III-b) and (III-c) except for using the pyridine derivative (1-axe2x80x2) in place of the pyridine derivative (1-a).
In the pyridine derivative (1) of the present invention, pyridine derivatives shown in the following items {circle around (3)} to {circle around (4)} may be produced by subjecting a pyridine (1-g) wherein Y in the group A2 is a group: xe2x80x94(CH2)mxe2x80x94 and at least one of R8 is a hydroxyl group or a pyridine (1-gxe2x80x2) wherein Y in the group A3 is a group: xe2x80x94(CH2)mxe2x80x94 and at least one of R9 is a hydroxyl group as a starting material to the dehydration reaction in a suitable solvent.
{circle around (3)} a pyridine derivative (1-c) wherein Y in the group A2 in A is a group: xe2x95x90CH(CH2)mxe2x80x94 or a group: xe2x80x94(CH2)m-1CHxe2x95x90 and at least one of R8 is a hydrogen atom
{circle around (4)} a pyridine derivative (1-cxe2x80x2) wherein Z in the group A3 in A is a group: xe2x95x90CH(CH2)n-1xe2x80x94 or a group: xe2x80x94(CH2n-1CHxe2x95x90 and at least one of R9 is a hydrogen atom
The process for synthesizing the above pyridine derivative (1-c) of the item {circle around (3)} will be explained by way of example.
Reaction Scheme (IV-a): 
(wherein R1, R2, R3, R8, V and m are as defined above)
According to this reaction, a pyridine derivative (1-c-1) wherein Y is a group: xe2x80x94(CH2)m-1CHxe2x95x90 is obtained by dehydrating a pyridine derivative (1-g-1) having a hydroxyl group in a suitable solvent, using a reaction reagent such as pyridinium bromide perbromide, dioxane dibromide, bromine, etc.
The solvent may be any one which does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; halogenated hydrocarbon such as methylene chloride, chloroform and carbon tetrachloride; aromatic hydrocarbon such as benzene and toluene; and acetic acid, trifluoroacetic acid and methanesulfonic acid.
The amount of pyridinium bromide perbromide used is usually from 1 to 5 mol, and preferably from 1 to 3 mol, per mol of the pyridine derivative (1-g-1). The reaction is usually carried out at xe2x88x9210 to 150xc2x0 C., and is completed within about 30 minutes to 24 hours.
A pyridine derivative (1-c-2) wherein Y is a group: xe2x95x90CH(CH2)m-1xe2x80x94 in the pyridine derivative (1-c) of the above item {circle around (1)} can be produced by reacting according to the same manner as that described in the reaction scheme (IV-a) except for using a pyridine derivative (1-g-2) represented by the general formula: 
(wherein R1, R2, R3, R8, V and m are as defined above) in place of the above pyridine derivative (1-g-1).
In the pyridine derivative (1) of the present invention, pyridine derivatives (1-d) to (1-e) and (1-dxe2x80x2) to (1-exe2x80x2) shown in the following items {circle around (5)} to {circle around (8)} may be produced by using, as a starting material, a pyridine derivative (1-h) wherein Y in the group A2 is a group: xe2x80x94(CH2)m-1xe2x80x94 and at least one of R8 is an oxo group or a pyridine derivative (1-hxe2x80x2) wherein Z in the group A3 is a group: xe2x80x94(CH2)nxe2x80x94 and at least one of R9 is an oxo group.
{circle around (5)} a pyridine derivative (1-d) wherein Y in the group A is a group: xe2x95x90CH(CH2)m-1xe2x80x94 or a group: xe2x80x94(CH2)m-1CHxe2x95x90 and at least one of R8 is a lower alkanoyloxy group
{circle around (6)} a pyridine derivative (1-dxe2x80x2) wherein Z in the group A3 is a group: xe2x95x90CH(CH2)n-1xe2x80x94 or a group: xe2x80x94(CH2)n-1CHxe2x95x90 and at least one of R8 is a lower alkanoyloxy group
{circle around (7)} a pyridine derivative (1-e) wherein Y in the group A2 is a group: xe2x95x90CH(CH2)m-1xe2x80x94 or a group: xe2x80x94(CH2)m-1CHxe2x95x90 and at least one of R8 is a lower alkoxy group
{circle around (8)} a pyridine derivative (1-exe2x80x2) wherein Z in the group A3 is a group: xe2x95x90CH(CH2)n-1xe2x80x94 or a group: xe2x80x94(CH2)n-1CHxe2x95x90 and at least one of R9 is a lower alkoxy group
The process for producing the pyridine derivatives (1-d) to (1-e) of the above items {circle around (5)} and {circle around (7)} will be explained by way of R8 in the group A2 as the example.
First, the process for producing the pyridine derivative (1-d) of the item {circle around (5)} will be explained by using the following reaction scheme (IV-b).
Reaction Scheme (IV-b): 
(wherein R1, R21, R3, R8, V and m are as defined above, and R8e represents a lower alkanoyloxy group)
According to this reaction, a pyridine derivative (1-d-1) wherein Y is a group: xe2x80x94(CH2)m-1CHxe2x95x90 and has a lower alkanoyloxy group is obtained by reacting a pyridine derivative (1-h-1) having an oxo group with an acylating agent in a state free from solvent or in a suitable solvent in the presence of an acid or a base.
The solvent may be any one which does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; halogenated hydrocarbon such as methylene chloride and chloroform; aromatic hydrocarbon such as benzene and toluene; and dimethylformamide and acetic acid.
The acylating agent includes acid anhydride, acid halide or esters (e.g. isopropenyl ester, etc.) corresponding to the alkanoyl moiety of R8e and examples thereof include acetic anhydride, acetyl halide, isopropenyl acetate, propionyl halide, isopropenyl propionate, isobutyryl halide, pivaloyl halide and hexanoyl halide.
Specifically explaining, acetic anhydride, isopropyl acetate and acetyl halide (e.g. acetyl chloride, acetyl fluoride, acetyl iodide, acetyl bromide, etc.) may be used as the acylating agent to obtain a pyridine derivative (1-d-11) wherein R8e is an acetyloxy group in the above pyridine derivative (1-d-1).
The acid includes, for example, Lewis acid such as boron trifluoride, boron trichloride, stannic chloride, titanium tetrachloride, boron trifluoride-ethyl ether complex and zinc chloride; hydrogen halide such as hydrogen chloride, hydrogen bromide, hydrogen fluoride and hydrogen iodide; inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid and sulfuric acid; organic acid such as trichloroacetic acid, trifluoroacetic acid and p-toluenesulfonic acid; and anion exchange resin.
The base includes, for example, trialkylamine (e.g. triethylamine, etc.), pyridine, dimethylaminopyridine, lithium diisoproylamide (LDA), potassium hydride, sodium hydride, sodium methoxide, potassium acetate, sodium acetate and cation exchange resin.
The amount of the acylating agent used is usually from 1 to 100 mol, and preferably from 2 to 5 mol, per mol of the pyridine derivative (1-h-1). The amount of the acid or base used is usually from 0.01 to 10 mol, and preferably from 0.02 to 0.1 mol, per mol of the pyridine derivative (1-h-1). The reaction is usually carried out under the conditions of xe2x88x9278 to 150xc2x0 C. for 1 minute to 3 days, and preferably about 15 minutes to 24 hours.
A pyridine derivative (1-d-2) wherein Y is a group: xe2x95x90CH(CH2)m-1xe2x80x94 in the pyridine derivative (1-d) of the above item {circle around (5)} can be produced by reacting according to the same manner as that described in the reaction scheme (IV-b) except for using a pyridine derivative represented by the general formula (1-h-2): 
(wherein R1,R2, R3, R8, V and m are as defined above) in place of the above pyridine derivative (1-h-1).
The pyridine derivative (1-dxe2x80x2) of the above item {circle around (6)} can be produced by reacting according to the same manner as that described in the reaction scheme (IV-b) except for using a pyridine derivative (1-hxe2x80x2) wherein at least one of R9 is an oxo group in place of the pyridine derivative (1-h-1).
The process for producing the pyridine derivative (1-e) of the above item {circle around (7)} will be explained below by using the following reaction scheme (IV-c).
Reaction Scheme (IV-c): 
(wherein R1, R2, R3, R8, V and m are as defined above, and R8f represents a lower alkoxy group)
According to this reaction, a pyridine derivative (1-e-1) having a lower alkoxy group is obtained by reacting the pyridine derivative (1-h-1) with an orthoformic acid lower alkyl ester in a suitable solvent in the presence of an acid. In that case, when anhydrous magnesium sulfate or 4A molecular sieve is added, water is easily removed from the reaction system and, therefore, the reaction proceeds.
The solvent may be any one which does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; lower alcohols such as methanol and ethanol; halogenated hydrocarbon such as methylene chloride and chloroform; aromatic hydrocarbon such as benzene and toluene; and nitromethane.
The acid includes, for example, Lewis acid (e.g. boron trifluoride, boron trichloride, stannic chloride, titanium tetrachloride, boron trifluoride-ethyl ether complex and zinc chloride, etc.), p-toluenesulfonic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, acetic acid and (xc2x1)-10-camphorsulfonic acid.
The lower alkyl orthoformate includes, for example, alkyl orthoformate whose alkyl moiety has 1 to 6 carbon atoms, such as methyl orthoformate, ethyl orthoformate, butyl orthoformate and hexyl orthoformate. Specifically explaining, ethyl orthoformate may be used as the lower alkyl orthoformate in the case of obtaining a pyridine derivative (1-e-11) wherein R8f is an ethoxy group in the above pyridine derivative (1-e-1).
The amount of the lower alkyl orthoformate used is usually from 1 to 100 mol, and preferably from 5 to 20 mol, per mol of the pyridine derivative (1-h-1).
The amount of the acid used is usually from 0.01 to 2 mol, and preferably from 0.1 to 1.5 mol, per mol of the pyridine derivative (1-h-1). The reaction is usually carried out at xe2x88x9278 to 150xc2x0 C., and is completed within about 1 minute to 24 hours.
A pyridine derivative (1-e-2) wherein Y is a group: xe2x95x90CH(CH2)m-1xe2x80x94 in the pyridine derivative (1-e) of the above item {circle around (7)} can be produced by reacting according to the same manner as that described in the reaction scheme (IV-c) except for using a pyridine derivative (1-h-2) in place of the above pyridine derivative (1-h-1).
The above pyridine derivative (1-exe2x80x2) of the item {circle around (8)} can be produced by reacting according to the same manner as that described in the reaction scheme (IV-c) except for using a pyridine derivative (1-hxe2x80x2) wherein at least one of R9 is an oxo group in place of the pyridine derivative (1-h-1).
Reaction Scheme (V): 
(wherein A and V are as defined above)
According to this reaction, the above compound (3) as a starting material of the reaction scheme (I-a) or reaction scheme (I-b) is obtained by reacting a monohalogenonitropyrodine (7) with a compound (8) to give a 3-nitropyridine derivative (9) and reducing this 3-nitropyridine derivative (9) in a suitable solvent using a catalytic reduction process, or reducing in the presence of an acid using a catalyst such as zinc, iron and tin.
The reaction for obtaining the 3-nitropyridine derivative (9) from the monohalogenonitropyridine derivative (7) and compound (8) is carried out in a state free from solvent, or in a suitable solvent. In that case, potassium carbonate or sodium carbonate may also be added to enhance nucleophilic property of the compound (8).
The solvent may be any one which does not adversely affect the reaction, and examples thereof include lower alcohols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbon such as methylene chloride and chloroform; and dimethylformamide and dimethyl sulfoxide.
The amount of the compound (8) used is usually 1 mol, and preferably from 1 to 5 mol, per mol of the monohalogenonitropyridine derivative (7).
The reaction is usually carried out at 0 to 150xc2x0 C., and preferably from 20 to 80xc2x0 C., and the reaction is completed within about 1 to 30 hours.
The reaction for obtaining a compound (3) from a 3-nitropyridine derivative (9) is carried out in a state free from solvent, or in a suitable solvent.
The solvent may be any one which does not adversely affect the reaction, and examples thereof include lower alcohols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; and dimethoxymethane, dimethoxyethane and water.
The amount of the reducing agent used is usually from 0.05 to 5 mol, and preferably from 0.2 to 3 mol, per mol of the 3-nitropyridine derivative (9).
The reaction is usually carried out at xe2x88x9210 to 150xc2x0 C., and preferably from 0 to 50xc2x0 C., and the reaction is completed within about 30 minutes to 30 hours.
An aminopyridine derivative (3-b) wherein R4 or R5 in the group A in A is a 2-lower alkyl-1,3-dioxolane group is synthesized by the following reaction scheme (VI). 
(wherein R11 represents a lower alkyl group)
That is, the above aminopyridine derivative (3-b) is obtained by reacting a nitro compound (9-a) with ethylene glycol in a suitable solvent in the presence of an acid to give a cyclic acetal (dioxolane) compound (9-b) and reducing this compound (9-b) according to the same manner as that described in the reaction scheme (V).
The solvent may be any one which does not adversely affect the reaction, and examples thereof include lower alcohols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbon such as benzene and toluene; and dimethoxyethane.
As the acid, for example, p-toluenesulfonic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, acetic acid and (xc2x1)-10-camphorsulfonic acid are preferably used. Among them, (xc2x1)-10-camphorsulfonic acid is preferably used.
The amount of ethylene glycol used is usually 1 mol, and preferably from 1 to 5 mol, per mol of the nitro compound (9-a).
The amount of the acid used is usually from 0.01 to 0.1 mol, and preferably from 0.01 to 0.05 mol, per mol of the nitro compound (9-a).
The reaction is usually carried out at xe2x88x9210 to 150xc2x0 C., and preferably from room temperature to 100xc2x0 C., and the reaction is completed within about 1 to 30 hours.
In the present invention, the pyridine derivative (1) wherein R4 or R5 in the group A1 in A is a 2-lower alkyl-1,3-dioxolane group of the present invention may be produced by using the aminopyridine derivative (3-b) obtained in the above reaction scheme (VI) as a starting material, or may also be produced by synthesizing a pyridine derivative wherein R4 or R5 in the group A1 in A is a lower alkanoyl group (with the proviso that a formyl group is eliminated) and converting said oxo group into a cyclic acetal according to the process described in the above reaction scheme (VI).
The pyridine derivative wherein R8 in the group A2 in A or R9 in the group A3 is a group: 
(wherein k is as defined above) can also be produced according to the same manner as that in case of R4 or R5 in the above group A1.
In the above 3-aminopyridine derivative (3), 3-aminopyridine derivatives (3-d) to (3-dxe2x80x2) shown in the following items (i) to (ii) may also be produced by using, as a starting material, a 3-nitropyridine derivative (9-c) wherein Y in the group A2 is a group: xe2x80x94(CH2)mxe2x80x94 and at least one of R8 is an oxo group or a 3-nitropyridine derivative (9-cxe2x80x2) wherein Z in the group A3 is a group: xe2x80x94(CH2)nxe2x80x94 and at least one of R9 is an oxo group.
(i) a 3-aminopyridine derivative (3-d) wherein Y in the group A2 in A is a group: xe2x95x90CH(CH2)m-1xe2x80x94 or a group: xe2x80x94(CH2)m-1CHxe2x95x90 and R8 is a lower alkanoyloxy group
(ii) a 3-aminopyridine derivative (3-dxe2x80x2) wherein Z in the group A3 in A is a group: xe2x95x90CH(CH2)n-1xe2x80x94 or a group: xe2x80x94(CH2)n-1CHxe2x95x90 and R9 is a lower alkanoyloxy group
The process: for producing 3-aminopyridine (3-d-1) wherein Y in the group A2 is a group: xe2x80x94(CH2)m-1CHxe2x95x90 of the above item (i) will be explained by way of example.
Reaction Scheme (VII-a): 
(wherein R8, m and R8e are as defined above)
That is, as shown in the above reaction scheme (VII-a), the 3-aminopyridine derivative (3-d-1) is obtained by reacting the 3-nitropyridine derivative (9-c-1) with an acylating agent to give a 3-nitropyridine derivative represented by the general formula (9-d-1) and reducing this compound (9-d-1) using a catalytic reduction process.
The reaction for obtaining the compound (9-d-1) from the 3-nitropyridine derivative (9-c-1) is carried out in a state free from solvent or in a suitable solvent in the presence of an acid or a base.
The solvent may be any one which does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; halogenated hydrocarbon such as methylene chloride and chloroform; aromatic hydrocarbon such as benzene and toluene; and dimethylformamide and acetic acid.
As the acylating agent, for example, acid anhydride, acid halide or esters (e.g. isopropenyl ester, etc.) corresponding to the alkanoyl moiety of R8e may be used. Specifically explaining, since the lower alkanoyl moiety of R8e is acetyl when obtaining a compound (3-d-11) wherein R8e is an acetyloxy group, for example, acetic anhydride, acetyl chloride and isopropenyl acetate may be used as the acylating agent (acetylating agent in this case).
The acid includes, for example, Lewis acid such as boron trifluoride, boron trichloride, stannic chloride, titanium tetrachloride, boron trifluoride-ethyl ether complex and zinc chloride; hydrogen halide such as hydrogen chloride, hydrogen bromide and hydrogen iodide; inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid and sulfuric acid; organic acid such as trichloroacetic acid, trifluoroacetic acid and p-toluenesulfonic acid; and anion exchange resin.,
The base includes, for example, trialkylamine (e.g. triethylamine, etc.), pyridine, dimethylaminopyridine, lithium diisoproylamide (LDA), potassium hydride, sodium hydride, sodium methoxide, potassium acetate, sodium acetate and cation exchange resin.
The amount of the acylating agent used is usually from 1 to 100 mol, and preferably from 2 to 5 mol, per mol of the 3-nitropyridine derivative (9-c-1). The amount of the acid or base used is usually from 0.01 to 10 mol, and preferably from 0.02 to 0.1 mol, per mol of the 3-nitropyridine derivative (9-c-1).
The reaction is usually carried out under the conditions of xe2x88x9278 to 150xc2x0 C. for 1 minute to 3 days, and preferably about 15 minutes to 24 hours.
The reaction for obtaining the compound (3-d-1) from the compound (9-d-1) is carried out in a suitable solvent. The solvent may be any one which does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF) and dioxane; and dimethoxyethane, diethoxyethane and water.
As the reducing agent used in the reduction includes, for example, platinum dioxide, palladium-carbon (Pdxe2x80x94C) and Raney nickel. Among them, platinum dioxide is superior in selective reduction.
The amount of the reducing agent used is usually from 0.01 to 5 mol, and preferably from 0.02 to 0.1 mol, per mol of the 3-nitropyridine derivative (9-d-1).
The reaction is usually carried out at xe2x88x9210 to 150xc2x0 C., and preferably from 0 to 50xc2x0 C., and the reaction is completed within about 10 minutes to 30 hours.
A pyridine derivative (3-d-2) wherein Y is a group: xe2x95x90CH(CH2)m-1 in the 3-aminopyridine derivative (3-d) of the above item (i) can be produced by reacting according to the same manner as that described in the reaction scheme (VII-a) except for using a 3-nitropyridine derivative represented by the general formula (9-c-2): 
(wherein R8 and m are as defined above) in place of the above 3-nitropyridine derivative (9-c-1).
The 3-aminopyridine derivative (3-dxe2x80x2) of the above item (ii) can be produced by reacting according to the same manner as that described in the reaction scheme (VII-a) except for using a 3-nitropyridine derivative (9-cxe2x80x2) in place of the 3-nitropyridine derivative (9-c-1).
In the 3-aminopyridine derivative (3), 3-aminopyrdine derivatives (3-e) to (3-exe2x80x2) shown in the following items (iii) to (iv) may also be produced by using, as a starting material, a 3-nitropyridine derivative wherein at least one of R8 is an acetyloxy group, such as compound (9-d-11) obtained by the above reaction scheme (VII-a), or 3-nitropyridine derivatives (9-dxe2x80x2-11) to (9-dxe2x80x2-21) wherein at least one of R8 is an acetyloxy group.
(iii) a 3-aminopyridine derivative (3-e) wherein Y in the group A2 in A is a group: xe2x95x90CH(CH2)m-1xe2x80x94 or a group: xe2x80x94(CH2)m-1CHxe2x95x90 and at least one of R8 is an aroyloxy group or a lower alkanoyloxy group except acetoxy group
(iv) a 3-aminopyridine derivative (3-exe2x80x2) wherein Z in the group A3 in A is a group: xe2x95x90CH(CH2)n-1xe2x80x94 or a group: xe2x80x94(CH2)n-1CHxe2x95x90 and at least one of R9 is an aroyloxy group or a lower alkanoyloxy group except acetoxy group
The process for producing 3-aminopyridine (3-e-1) wherein Y in the group A2 is a group: xe2x80x94(CH2)m-1CHxe2x95x90 of the above item (iii) will be explained by using the following reaction scheme (VII-b).
Reaction Scheme (VII-b): 
(wherein R8 and m are as defined above, and R8g represents an aroyloxy group or a lower alkanoyloxy group except acetoxy group)
According to this reaction, the above 3-aminopyridine derivative (3-e-1) is obtained by reacting a compound (9-d-11) obtained in the reaction scheme (VII-a) with an acid halide in a state free from solvent or in a suitable solvent in the presence of an acid to give a compound represented by the general formula (9-f-1) and reducing this compound (9-f-1) using a catalytic reduction process according to the same manner as that in case of the reaction scheme (VII-a).
The solvent may be any one which does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; halogenated hydrocarbon such as carbon tetrachloride, methylene chloride and chloroform; and aromatic hydrocarbon such as benzene and toluene.
As the acid halide, for example, acid halide corresponding to the acyl moiety of R8g may be used, and examples thereof include propionyl halide, isobutyryl halide, pivaloyl halide, hexanoyl halide and benzoyl halide. Specifically explaining, benzoyl halide such as benzoyl chloride, benzoyl bromide, benzoyl iodide and benzoyl fluoride may be used when obtaining a compound (3-e-11) wherein the acyl moiety of the acyloxy group is benzoyl.
The acid includes, for example, Lewis acid such as boron trifluoride, boron trichloride, stannic chloride, titanium tetrachloride, boron trifluoride-ethyl ether complex and zinc chloride; hydrogen halide such as hydrogen chloride, hydrogen bromide, hydrogen fluoride and hydrogen iodide; inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid and sulfuric acid; organic acid such as trichloroacetic acid, trifluoroacetic acid and p-toluenesulfonic acid; and anion exchange resin.
The amount of the acid halide used is usually from 1 to 100 mol, and preferably from 5 to 10 mol, per mol of the 3-nitropyridine derivative (9-d-11). The amount of the acid or base used is usually from 0.01 to 10 mol, and preferably from 0.02 to 0.1 mol, per mol of the 3-nitropyridine derivative (9-d-11).
The reaction is usually carried out under the conditions of xe2x88x9278 to 150xc2x0 C. for 1 minute to 3 days, and preferably about 15 minutes to 24 hours.
A pyridine derivative (3-e-2) wherein Y is a group: xe2x95x90CH(CH2)m-1xe2x80x94 in the 3-aminopyridine derivative (3-e) of the above item (iii) can be produced by reacting according to the same manner as that described in the reaction scheme (VII-b) except for using a pyridine derivative represented by the general formula (9-d-21): 
(wherein R8 and m are as defined above) in place of the above pyridine (9-d-11).
The 3-aminopyridine derivative (3-exe2x80x2) of the above item (iv) can be produced by reacting according to the same manner as that described in the reaction scheme (VII-b) except for using a pyridine derivative (9-dxe2x80x2-11) or (9-dxe2x80x2-21) wherein Z is a group: xe2x95x90CH(CH2)n-1xe2x80x94 or a group: xe2x80x94(CH2)n-1CHxe2x95x90 and at least one of R9 is an acetyloxy group in place of the above pyridine derivative (9-d-11)
Reaction Scheme (VIII): 
(wherein A, X and R11 are as defined above)
According to this reaction, the above carboxylic acid (5) as a starting material of the reaction scheme (II) is obtained by reacting a monohalogenopyridinecarboxylate (10) with a compound (8) to give a pyridinecarboxylate derivative (11) and hydrolyzing a protective group in this compound (11).
To obtain the pyridinecarboxylate derivative (11) from the monohalogenopyridinecarboxylate (10), the reaction may be carried out according to the same manner as that described in the above reaction scheme (V).
The amount of the compound (8) used is usually 1 mol, and preferably from 1 to 5 mol, per mol of the monohalogenopyridinecarboxylate (10).
The reaction is usually carried out at 0 to 150xc2x0 C., and preferably from 20 to 80xc2x0 C., and the reaction is completed within 1 to 30 hours.
The pyridinecarboxylate derivative (11) is hydrolyzed in a suitable solvent in the presence of a basic compound.
The basic compound includes, for example, alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; alkali metal carbonate such as sodium carbonate and potassium carbonate; alkali metal hydrogencarbonate such as sodium hydrogencarbonate and potassium hydrogencarbonate; trialkylamine such as triethylamine and tributylamine; and organic base such as pyridine, picoline and 1,4-diazabicyclo[2.2.2]octane.
The solvent may be any one which does not adversely affect the reaction, and examples thereof include lower alcohols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran (THF) and dioxane; water or a mixed solvent thereof.
This hydrolysis reaction is usually carried out at xe2x88x9210 to 200xc2x0 C., and preferably from 30 to 60xc2x0 C., and the reaction is completed within about 30 minutes to 24 hours.

(wherein R1, R2, R3 and A are as defined above)
This reaction is a process for obtaining a pyridine derivative (13) which is a compound wherein V is xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 in the general formula (1).
According to this reaction, the urea derivative (13) is obtained by the addition of 3-amino-pyridine derivative (3) to the isocyanato compound (12) in a state free from solvent or in an inert solvent: and amines may be added in the reaction system.
The solvents include, for example, benzene, toluene, chlorobenzene, dichloromethane, acetone or tetrahydrofuran and the like. The amines include, for example, tertiary amines such as triethylamine, triisopropylamine and pyridine. The amount of the amine used is usually from 1 to 5 mol, and preferably from 1 to 2 mol, per mol of the isocynato compound (12).
The 3-amino-pyridine derivative (3) used is usually from 1 to 10 mol, and preferably 1 to 3 mol, per mol of the isocyanato compound (12). The reaction is usually carried out under the conditions of xe2x80x9410 to 150xc2x0 C., and is completed within 10 minutes to 24 hours.
Reaction Scheme (X): 
According to this reaction, a compound (15) is obtained by saponifying an enol ester derivative (14) using an alkali, and the reaction is carried out in a suitable solvent. The alkali includes, for example, hydroxide of alkali metal, salts, hydroxide of alkali earth metal, salts, and amines. The solvent may be a protonic solvent, and examples thereof include water; alcohols such as methanol and dioxane; and a mixed solvent of these solvents and ethers such as tetrahydrofuran and dioxane, acetonitrile and dimethylformamide. The amount of the alkali used is usually from 1 to 10 mol, and preferably from 1 to 3 mol, per mol of the compound (14). The reaction is usually carried out at xe2x88x9210 to 150xc2x0 C., and is completed within about 30 minutes to 24 hours.
Reaction Scheme (XI): 
This reaction is a process for obtaining a pyridine derivative (18) which is a compound wherein V is xe2x80x94CHxe2x95x90CHxe2x80x94 in the general formula (1).
According to this reaction, the pyridine derivative (18) is obtained by subjecting phosphorus-ylide generated from the compound (16) to condensation (Witting reaction) with the aldehyde compound (17).
The phosphorus-ylide is generated from the phosphonium salt (16) under anhydrous condition with a suitable combination of a base and a solvent.
The combination of a base and a solvent includes, for example, sodium ethoxide-ethanol, N,N-dimethylformamide; sodium methoxide-methanol-ether, N,N-dimethylformamide; potassium t-butoxide-tetrahydrofuran, dichloromethane; n-butyl lithium-ether; phenyl lithium-ether and the like. The base used is usually from 1 to 10 mol, and preferably 1 to 2 mol, per mol of the phosphonium salt (16). The reaction is usually carried out at xe2x88x9210 to 150xc2x0 C., and is completed within 30 minutes to 24 hours. The phosphorus-ylide is reacted with the aldehyde compound (17) in a solvent mentioned above, and the compound (17) used is usually from 1 to 10 mol, and preferably 1 to 3 mol, per mol of the compound (16). The reaction is carried out at xe2x88x9210 to 150xc2x0 C., and is completed within 30 minutes to 24 hours.
A salt of the pyridine derivative (1) in the present invention includes a pharmaceutically acceptable salt. Such a salt include, for example, inorganic acid salt such as hydrochloride, hydrobromide, nitrate, sulfate and phosphate; and organic acid salt such as methanesulfonate, p-toluenesulfonate, acetate, citrate, tartrate, maleate, fumarate, malate and lactate.
A pharmaceutical preparation containing the pyridine derivative (1) or a pharmaceutical acceptable salt thereof as an active ingredient will be explained below.
The pharmaceutical preparation is prepared in the form of a usual pharmaceutical preparation by using the pyridine derivative (1) of the present invention, and is usually prepared by using diluents and/or excipients, such as a fillers, extenders, binders, humectants, disintegrators, surfactants and lubricants, which are usually used.
The pharmaceutical preparation can be selected from various forms according to the purpose of treating, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories and injections (e.g. solution, suspension, etc.).
In the case of forming into tablets, conventionally known one can be widely used as a carrier. For example, there can be used excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinyl pyrrolidone; disintegrators such as dried starch, sodium alginate, agar powder, laminarin powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty esters, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegration inhibitors such as sucrose, stearin, cacao butter and hydrogenated oil; absorption accelerators such as quaternary ammonium base and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; and lubricants such as purified talc, stearate, boron powder and polyethylene glycol. If necessary, tablets can be subjected to tablet coating to form sugar coated tablets, gelatin coated tablets, enteric coated tablets, film coated tablets, or two-layer tablets and multilayer tablets.
In the case of forming into pills, conventionally known one can be widely used as a carrier. For example, there can be used excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin and talc; binders such as arabic gum powder, powdered tragacanth, gelatin and ethanol; and disintegrators such as laminarin and agar.
In the case of forming into suppositories, conventionally known one can be widely used as a carrier. For example, there can be used polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, semisynthetic and glyceride.
In the case of preparing injections, for example, solutions, emulsions and suspensions are preferably sterilized and are isotonic with blood. In the case of forming into the form of solutions, emulsions and suspensions, conventionally known one can used as a diluent. For example, there can be used water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and polyoxyethylene sorbitan fatty esters. In this case, sodium chloride, glucose or glycerin may also be contained in the pharmaceutical preparation in the amount enough to prepare an isotonic solution. Furthermore, normal solubilizers, buffers and soothing agents may also be contained and, if necessary, colorants, preservatives, perfumes, flavors, sweeteners and other pharmaceuticals may also be contained.
The amount of the pyridine derivative (1) or a salt thereof to be contained in the pharmaceutical preparation can not be specifically limited and selected widely, but is preferably from 1 to 70% by weight based on the total composition.
The process for administration of the pharmaceutical preparation of the present invention is not specifically limited and the pharmaceutical preparation is administered according to the various preparation forms, age and sex of patients, conditions of diseases and other conditions. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered.
Injections are administered intravenously as they are, or after combining with a normal replenisher such as glucose and amino acid. Furthermore, injections can be administered alone, intramuscularly, intracutaneously or subcutaneously, if necessary. Suppositories are administered intrarectally.
The dosage of the pharmaceutical preparation may be appropriately selected according to direction for use, age and sex of patients, conditions of diseases, and other conditions, and the pharmaceutical preparation is administered 1 to several times per day with a dairy dose ranging from 0.01 to 100 mg/kg, and preferably from 0.1 to 50 mg/kg.
As a matter of course, since the dosage varies depending upon various conditions, the dosage is sometimes sufficient when the dosage is smaller than the above range, or the dosage exceeding the above range is sometimes required.